1. FIELD OF THE INVENTION
This invention relates to the preparation of 3-alkyl- or fluroalkyl-3-(4-pyridyl) piperidine-2, 6-diones of formula (1): ##STR2## wherein R represents an alkyl group having 2 to 10 carbon atoms or a fluoroalkyl group having 2 to 5 carbon atoms, and A represents hydrogen or an alkyl group having 1 to 4 carbon atoms, many of which are known compounds, useful in anti-cancer therapy, specifically the treatment of oestrogen-dependent breast tumours.
2. DESCRIPTION OF THE PRIOR ART
The compound of formula (1) wherein R is ethyl and X is hydrogen is 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione, conveniently called "pyridogluthethimide" for short, and is the subject of UK Pat. No. 2151226 B (NRDC). The same patent also covers derivatives thereof wherin A is alkyl of 1 to 4 carbon atoms. Analogues of pyridogluthethimide in which R is an alkyl group having 3 to 10 carbon atoms or a fluoroalkyl group having 2 to 5 carbon atoms are the subject of UK Pat. No. 2162177 B (NRDC).
In UK Pat. No. 2151226 B pyridoglutethimide is prepared by a 3-step process illustrated by Scheme 1 below: ##STR3## This method of preparation suffers from the disadvantage that the starting 4-pyridylacetonitrile is readily dialkylated, leading to a poor yield requiring a separation step.
In the final stage of Scheme 1, the reaction can be visualised as proceeding by a mechanism in which the cyano groups are hydrolysed to amido groups and then cyclised to single amido group with elimination of a molecule of ammonia. UK Pat. No. 2151226 B generalises on this reaction scheme as involving the cyclisation of a compound of formula (2): ##STR4## wherein at least one of Y and Z is cyano or amido and the other, if not also cyano or amido, can be a carboxylic acid group or a non-amide derivative thereof such as an ester. The preparation of compounds of formula (2) in which Y and Z are other than cyano is not described.
UK Pat. No. 2162177 B describes an improved method of carrying out the first step of Scheme 1, in which 4-pyridylacetronitrile is reacted with a primary alcohol, a trivalent rhodium salt and triphenylphosphine under mildly alkaline conditions. This gives the monoalkylated product, substantially free of dialkylated by-product. Other compounds were made using an alkyl bromide or fluoroalkyl iodide and caesium carbonate in the first step of Scheme 1. However, rhodium and caesium salts are relatively expensive reagents.